COMPLEXATION BETWEEN LOCAL-ANESTHETICS AND BETA-CYCLODEXTRIN DERIVATIVES - RELATIONSHIP BETWEEN STABILITY-CONSTANTS AND IN-VITRO MEMBRANE-PERMEABILITY OF BUPIVACAINE AND LIDOCAINE FROM THEIR COMPLEXES

The binding of two local anaesthetic drugs, bupivacaine and lidocaine with beta-cyclodextrin neutral derivatives (hydroxypropyl-beta-cyclode xtrin or dimethyl-beta-cyclodextrin) or an anionically charged derivat ive (sulfobutyl ether 7-beta-cyclodextrin was determined rising the ph ase solubility method. In order to mimic in vivo systemic absorption, we used an in vitro two-compartment model. Solutions of drugs with or without cyclodextrins were placed in the donor compartment; the concen tration in the sink aqueous acceptor was spectrophotometrically assaye d at 205 nm. Solubility studies for bath local anaesthetics under thei r base form suggested the formation of 1/1 complexes with all cyclodex trins tested. Moreover, the cyclodextrins were able to retain both dru gs in the donor compartment, as shown by the lower permeability coeffi cient values, especially as the stability constant was high. Concernin g bupivacaine hydrochloride, complexation with neutral cyclodextrins w as weaker compared to the base form, but a higher stability constant v alue was obtained with anionically charged sulfobutyl ether 7-beta-cyc lodextrin. Each time complexation occurred the rate limiting step of t he phenomenon was the dissociation of the complex, not diffusion acros s the membrane. In vivo study is in progress to confirm the interest o f cyclodextrins for site-specific delivery of drugs characterized by r apid systemic absorption producing side effects.